Title:

Level of physical activity in chronic stroke patients at tertiary care

hospitals in Peshawar: A cross-sectional study

Introduction:
Stroke is a neurological disorder characterized by blockage of blood vessels. Clots form in the
brain and interrupt blood flow, clogging arteries and causing blood vessels to break, leading
to bleeding. Rupture of the arteries leading to the brain during stroke results in the sudden
death of brain cells owing to a lack of oxygen. Stroke can also lead to depression and
dementia.
Until the international classification of disease 11 (icd-11) was released in 2018, stroke was
classified as a disease of the blood vessels. Under the previous icd coding rationale, clinical
data generated from stroke patients were included as part of the cardiovascular diseases
chapter, greatly misrepresenting the severity and specific disease burden of stroke. Due to this
misclassification within the icd, stroke patients and researchers did not benefit from
government support or grant funding directed towards neurological disease. After prolonged
advocacy from a group of clinicians, the true nature and significance of stroke was
acknowledged in the icd-11; stroke was re-categorized into the neurological chapter [1]. The
reclassification of stroke as a neurological disorder has led to more accurate documentation of
data and statistical analysis, supporting improvements in acute healthcare and acquisition of
research funding for stroke.
Epidemiology of stroke
Stroke is the second leading cause of death globally. It affects roughly 13.7 million people
and kills around 5.5 million annually. Approximately 87% of strokes are ischemic infarctions,
a prevalence which increased substantially between 1990 and 2016, attributed to decreased
mortality and improved clinical interventions. Primary (first-time) hemorrhages comprise the
majority of strokes, with secondary (second-time) hemorrhages constituting an estimated 10–
25% [2,3]. The incidence of stroke doubled in low-and-middle income countries over 1990–
2016 but declined by 42% in high-income countries over the same period. According to the
global burden of disease study (gbd), although the prevalence of stroke has decreased, the age
of those affected, their sex and their geographic location mean that the socio-economic
burden of stroke has increased over time [3]
Types of stroke
There are three main types of stroke:
Ischemic stroke: This is the most common type of stroke, making up 87% of all cases. A
blood clot prevents blood and oxygen from reaching an area of the brain.
Hemorrhagic stroke: This occurs when a blood vessel ruptures. These are usually the result
of aneurysms or arteriovenous malformations (avms)trusted source.
Transient ischemic attack (tia): This occurs when blood flow to a part of the brain is
inadequate for a brief period of time. Normal blood flow resumes after a short amount of
time, and the symptoms resolve without treatment. Some people call this a ministroke.

Pathophysiology of stroke:
Stroke is defined as an abrupt neurological outburst caused by impaired perfusion through the
blood vessels to the brain. It is important to understand the neurovascular anatomy to study
the clinical manifestation of the stroke. The blood flow to the brain is managed by two
internal carotids anteriorly and two vertebral arteries posteriorly (the circle of willis).
Ischemic stroke is caused by deficient blood and oxygen supply to the brain; hemorrhagic
stroke is caused by bleeding or leaky blood vessels.
Ischemic occlusions contribute to around 85% of casualties in stroke patients, with the
remainder due to intracerebral bleeding. Ischemic occlusion generates thrombotic and
embolic conditions in the brain [4]. In thrombosis, the blood flow is affected by narrowing of
vessels due to atherosclerosis. The build-up of plaque will eventually constrict the vascular
chamber and form clots, causing thrombotic stroke. In an embolic stroke, decreased blood
flow to the brain region causes an embolism; the blood flow to the brain reduces, causing
severe stress and untimely cell death (necrosis). Necrosis is followed by disruption of the
plasma membrane, organelle swelling and leaking of cellular contents into extracellular space
and loss of neuronal function[5]. Other key events contributing to stroke pathology are
inflammation, energy failure, loss of homeostasis, acidosis, increased intracellular calcium
levels, excitotoxicity, free radical-mediated toxicity, cytokine-mediated cytotoxicity,
complement activation, impairment of the blood–brain barrier, activation of glial cells,
oxidative stress and infiltration of leukocytes [6,7,8,9,10].
Hemorrhagic stroke accounts for approximately 10–15% of all strokes and has a high
mortality rate. In this condition, stress in the brain tissue and internal injury cause blood
vessels to rupture. It produces toxic effects in the vascular system, resulting in infarction [ 11].
It is classified into intracerebral and subarachnoid hemorrhage. In ich, blood vessels rupture
and cause abnormal accumulation of blood within the brain. The main reasons for ich are
hypertension, disrupted vasculature, excessive use of anticoagulants and thrombolytic agents.
In subarachnoid hemorrhage, blood accumulates in the subarachnoid space of the brain due to
a head injury or cerebral aneurysm [12,13].

Risk factors for stroke

As noted earlier, the risk of stroke increases with age and doubles over the age of 55 years in
both men and women. Risk is increased further when an individual has an existing medical
condition like hypertension, coronary artery disease or hyperlipidemia. Nearly 60% of strokes
are in patients with a history of transient ischemic attack (tia). Some of the risk factors for
stroke are modifiable, and some are non-modifiable .
Non-Modifiable risk factors
These include age, sex, ethnicity, tia and hereditary characteristics. In the us in 2005, the
average age of incidence of stroke was 69.2 years [2,14,15]. Recent research has indicated
that people aged 20–54 years are at increasing risk of stroke, probably due to pre-existing
secondary factors [16]. Women are at equal or greater risk of stroke than men, irrespective of
age [17]. Us research shows that hispanic and black populations are at higher risk of stroke
than white populations; notably, the incidence of hemorrhagic stroke is significantly higher in
black people than in age-matched white populations [18,19,20].
Transient ischemic attack is classified as a mini stroke; the underlying mechanism is the same
as for full-blown stroke. In tia, the blood supply to part of the brain is blocked temporarily. It
acts as a warning sign before the actual event, providing an opportunity to change lifestyle
and commence medications to reduce the chance of stroke [21,22]
Genetics contribute to both modifiable and non-modifiable risk factors for stroke. Genetic risk
is proportional to the age, sex and race of the individual [23,24], but a multitude of genetic
mechanisms can increase the risk of stroke. Firstly, a parental or family history of stroke
increases the chance of an individual developing this neurological disorder. Secondly, a rare
single gene mutation can contribute to pathophysiology in which stroke is the primary clinical
manifestation, such as in cerebral autosomal dominant arteriopathy. Thirdly, stroke can be
one of many after-effects of multiple syndromes caused by genetic mutation, such as sickle
cell anemia. Fourthly, some common genetic variants are associated with increased stroke
risk, such as genetic polymorphism in 9p21 [25]. A genome-wide association study of stroke
showed high heritability (around 40%) for large blood vessel disease, and low heritability
(16.7%) for small vessel disorders. Recent evidence suggests that studying heritability will
improve the understanding of stroke sub-types, improve patient management and enable
earlier and more efficient prognosis [5,26].
Modifiable risk factors:
These are of paramount importance, because timely and appropriate medical intervention can
reduce the risk of stroke in susceptible individuals. The major modifiable risk factors for
stroke are hypertension, diabetes, lack of physical exercise, alcohol and drug abuse,
cholesterol, diet management and genetics.
Hypertension: It is one of the predominant risk factors for stroke. In one study, a blood
pressure (bp) of at least 160/90 mmhg and a history of hypertension were considered equally
important predispositions for stroke, with 54% of the stroke-affected population having these
characteristics [27,28]. Bp and prevalence of stroke are correlated in both hypertensive and
normal individuals. A study reported that a 5–6 mm hg reduction in bp lowered the relative
risk of stroke by 42% [44]. Randomized trials of interventions to reduce hypertension in
people aged 60+ have shown similar results, lowering the incidences of symptoms of stroke
by 36% and 42%, respectively [29,30].
Diabetes: It doubles the risk of ischemic stroke and confers an approximately 20% higher
mortality rate. Moreover, the prognosis for diabetic individuals after a stroke is worse than for
non-diabetic patients, including higher rates of severe disability and slower recovery [47,48].
Tight regulation of glycemic levels alone is ineffective; medical intervention plus behavioral
modifications could help decrease the severity of stroke for diabetic individuals [31].
Atrial fibrillation (af): Af is an important risk factor for stroke, increasing risk two- to five-
fold depending upon the age of the individual concerned [32]. It contributes to 15% of all
strokes and produces more severe disability and higher mortality than non-af-related strokes
[33]. Research has shown that in af, decreased blood flow in the left atrium causes
thrombolysis and embolism in the brain. However, recent studies have contradicted this
finding, citing poor evidence of sequential timing of incidence of af and stroke, and noting
that in some patients the occurrence of af is recorded only after a stroke. In other instances,
individuals harboring genetic mutations specific to af can be affected by stroke long before
the onset of af [34,35]. Therefore, we need better methods of monitoring the heart rhythms
that are associated with the vascular risk factors of af and thromboembolism.
Hyperlipidemia: It is a major contributor to coronary heart disease, but its relationship to
stroke is complicated. Total cholesterol is associated with risk of stroke, whereas high-density
lipoprotein (hdl) decreases stroke incidence [36,37,38]. Therefore, evaluation of lipid profile
enables estimation of the risk of stroke. In one study, low levels of hdl (<0.90 mmol/l), high
levels of total triglyceride (>2.30 mmol/l) and hypertension were associated with a two-fold
increase in the risk of stroke-related death in the population [37].
Alcohol and drug abuse: The relationship between stroke risk and alcohol intake follows a
curvilinear pattern, with the risk related to the amount of alcohol consumed daily. Low to
moderate consumption of alcohol (≤2 standard drinks daily for men and ≤1 for women)
reduces stroke risk, whereas high intake increases it. In contrast, even low consumption of
alcohol escalates the risk of hemorrhagic stroke [39,40,41]. Regular use of illegitimate
substances such as cocaine, heroin, phencyclidine (pcp), lysergic acid diethylamide (lsd),
cannabis/marijuana or amphetamines is related to increased risk of all subtypes of strokes
[42]. Illicit drug use is a common predisposing factor for stroke among individuals aged
below 35 years. Us research showed that the proportion of illicit drug users among stroke
patients aged 15–44 years was six times higher than among age-matched patients admitted
with other serious conditions [43]. However, there is no strong evidence to confirm these
findings, and the relationship between these drugs and stroke is anecdotal [44].
Smoking: Tobacco smoking is directly linked to increased risk of stroke. An average smoker
has twice the chance of suffering from a stroke of a non-smoker. Smoking contributes to 15%
of stroke-related mortality. Research suggests that an individual who stops smoking reduces
the relative risk of stroke, while prolonged second-hand smoking confers a 30% elevation in
the risk of stroke [45,46,47].
Insufficient physical inactivity and poor diet are associated with increased risk for stroke.
Lack of exercise increases the chances of stroke attack in an individual. Insufficient physical
activity is also linked to other health issues like high bp, obesity and diabetes, all conditions
related to high stroke incidence [48,49]. Poor diet influences the risk of stroke, contributing to
hypertension, hyperlipidemia, obesity and diabetes. Certain dietary components are well
known to heighten risk; for example, excessive salt intake is linked to high hypertension and
stroke. Conversely, a diet high in fruit and vegetables (notably, the mediterranean diet) has
been shown to decrease the risk of stroke [50,51,52,53,54].

Phases of stoke
Stroke management is typically categorized into three primary phases .
Acute phase
The first is the acute phase which refers to the initial period immediately after a stroke occurs.
It typically lasts for the first few hours or days. During this phase, the focus is on urgent
medical intervention to minimize brain damage and restore blood flow to the affected area.
Subacute phase
The subacute phase is the period that follows the acute phase, typically starting a few days
after the stroke and lasting up to several weeks or months. It is believed that this is a time
when the brain is most primed for recovery, where the brain restructures its functions,
adjusting to the damage from the stroke.
Chronic phase
The chronic phase begins after the subacute phase and represents the long-term phase of
stroke recovery. It encompasses the period of months to years after the stroke. In the chronic
phase, the focus is on continued rehabilitation, management of residual symptoms, and long-
term support for the individual's physical, cognitive, and emotional well-being.

Figure 1 - timeline of stroke recovery:

Prevention and treatment strategies for stroke:

Stroke prevention involves modifying risk factors within a population or individuals, while
stroke management depends on treating its pathophysiology. Despite an enormous amount of
research into stroke over the last two decades, no simple means of treating or preventing all
the clinical causes of stroke has been established.
Excitotoxicity: Neuronal death is a key manifestation of stroke. A key reason for this
phenomenon is neuronal depolarization and inability to maintain membrane potential within
the cell. This process is mediated by glutamate receptors n-methyl-d-aspartate (nmda) and α-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (ampa), which were among the first
neuroprotective agents tested in stroke prevention. However, the untimely release of
glutamate overpowers the system that removes glutamate from the cell and causes abnormal
release of nmda and ampa molecules, leading to uninhibited calcium influx and protein
damage. As a result, these agents have not been shown to reduce neuronal death in human
subjects. Targeting the molecular pathways downstream of excitotoxicity signaling, rather
than directly targeting glutamatergic signaling, might reduce the side effects of the process
[55,56].
Gamma aminobutyric acid (gaba) agonists: Clomethiazole is a gaba agonist that has been
tested for its ability to improve stroke symptoms in patients, but failed to reduce the toxicity
induced by the glutamate receptor [57].
Sodium (na+) channel blockers: Na+ channel blockers have been used as neuroprotective
agents in various animal models of stroke. They prevent neuronal death and reduce white
matter damage. Many voltage-gated na+ channel blockers have been tested in clinical trials,
but most have proved to be ineffective [58]. Mexiletine is a neuroprotectant and na+ channel
blocker that proved effective in grey and white matter ischemic stroke, though further
evaluation is required to confirm its role [59]. Lubeluzole was shown to reduce mortality in
stroke in initial clinical trials, but successive trials failed to reproduce similar outcomes.
Similarly, sipatrigine is a na+ and ca2+channel blocker which failed in a phase ii clinical trial
in stroke patients. Amiodarone was shown to aggravate brain injury due to defective
transportation and accumulation of na+ ions in the brain after stroke [60].
Calcium (ca2+) channel blockers: Voltage-dependent ca2+ ion channel blockers have been
shown to decrease the ischemic insult in animal models of brain injury. The ca2+ ion chelator
dp-b99 proved efficient and safe in phase i and ii clinical trials when administered to stroke
patients. Similarly, phase ii trials significantly improved clinical symptoms in stroke patients
treated within 12 h of onset [61]. In another study, ca2+ channel blockers reduced the risk of
stroke by 13.5% in comparison to diuretics and β-blockers [62].
Antioxidants: Reactive oxygen species produced in the normal brain are balanced by
antioxidants generated in a responsive mechanism. However, in the ischemic stroke model,
excess production of free radicals and inactivation of detoxifying agents cause redox
disequilibrium. This phenomenon leads to oxidative stress, followed by neuronal injury.
Therefore, antioxidants are employed in treatment of acute stroke to inhibit or scavenge free
radical production and degrade free radicals in the system. In one study, antioxidant aeol
10,150 (manganese (iii) meso-tetrakis (di-n-ethylimidazole) porphyrin) effectively regulated
the gene expression profiles specific to inflammation and stress response to decrease the
ischemic damage and reperfusion in stroke patients [63]. In another, deferoxamine was shown
to regulate the expression of hypoxia-inducible factor-1, a transcriptional factor regulated by
oxygen levels, which in turn switched on other genes like vascular endothelial growth factor
and erythropoietin. This mechanism, studied in an animal stroke model, proved beneficial in
reducing lesion size and improving sensorimotor capabilities [64,65]. Similarly, nxy-059
compound acts as a scavenger to eliminate free radicals and decrease neurological deficits.
The stroke-acute-ischemic-nxy-treatment-i (saint) clinical trial showed the efficacy and safety
of nxy-059, but saint ii failed to reproduce the positive effect of this drug in stroke patients
[66,67]. In another study, researchers employed intravenous injection of antioxidants directly
into mice brains to understand the benefits of route of administration. This method reduced
neurological defects, but had minimal influence on brain damage [68].
Rehabilitation: Stroke can leave individuals with short- and long-term disabilities. Daily
activities like walking and toileting are often affected, and sensorimotor and visual
impairment are common. Rehabilitation aims to reinforce the functional independence of
people affected by stroke [69]. It includes working with patients and families to provide
supportive services and post-stroke guidance after 48 h of stroke attack in stable patients.
Stroke rehabilitation may involve physical, occupational, speech and/or cognitive therapy. It
is designed to assist patients to recover problem-solving skills, access social and
psychological support, improve their mobility and achieve independent living. Rehabilitation
may also include neurobiological tasks designed to lessen the impact of cognitive dysfunction
and induce synaptic plasticity, as well as long-term potentiation [70,71]. Neuromodulators
play a vital role in triggering expression of specific genes that promote axon regeneration,
dendritic spine development, synapse formation and cell replacement therapy. Task-oriented
approaches, like arm training and walking, help stroke patients to manage their physical
disability, and visual computer-assisted gaming activities have been used to enhance
visuomotor neuronal plasticity [72].

Physical activity
WHO defines physical activity as “ any bodily movement produce by skeletal muscles that
requires energy expenditure” Is called physical activity.

The common disabilities of individuals with stroke are usually associated with low physical
activity levels.[73,74,75] maintaining a good physical activity level after experiencing a
stroke has the potential to improve general health and function,[74,76] with a reduction of the
risk factors for stroke, such as hypertension and lipid dysfunction, and in the likelihood of
recurrent stroke. [76,77]

Rationale
Literature shows limited studies done on level of physical activity in chronic stroke patients.
Pakistan has high rates of strokes still it lacks sufficient data about its level of physical
activity. This study was conducted to find out the level of physical activity in chronic stroke
patients in tertiary care hospitals in Peshawar.
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